Sun Mengxi, Cui Wenqi, Woody Sarah K, Staudinger Jeff L
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas.
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas
Drug Metab Dispos. 2015 Mar;43(3):335-43. doi: 10.1124/dmd.114.062307. Epub 2014 Dec 19.
Bacterial sepsis is characterized by a rapid increase in the expression of inflammatory mediators to initiate the acute phase response in liver. Inflammatory mediator release is counterbalanced by the coordinated expression of anti-inflammatory molecules such as interleukin 1 receptor antagonist (IL1-Ra) through time. This study determined whether activation of pregnane X receptor (PXR, NR1I2) alters the lipopolysaccharide (LPS)-inducible gene expression program in primary cultures of hepatocytes (PCHs). Preactivation of PXR for 24 hours in PCHs isolated from wild-type mice suppressed the subsequent LPS-inducible expression of the key inflammatory mediators interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNFα) but not in PCHs isolated from Pxr-null (PXR-knockout [KO]) mice. Basal expression of key inflammatory cytokines was elevated in PCHs from PXR-KO mice. Stimulation of PCHs from PXR-KO mice with LPS alone produced enhanced levels of IL-1β when compared with wild-type mice. Experiments performed using PCHs from both humanized-PXR transgenic mice as well as human donors indicate that prolonged activation of PXR produces an increased secretion of IL1-Ra from cells through time. Our data reveal a working model that describes a pivotal role for PXR in both inhibiting as well as in resolving the inflammatory response in hepatocytes. Understanding the molecular details of how PXR is converted from a positive regulator of drug-metabolizing enzymes into a transcriptional suppressor of inflammation in liver will provide new pharmacologic strategies for modulating inflammatory-related diseases in the liver and intestine.
细菌性败血症的特征是炎症介质的表达迅速增加，从而启动肝脏中的急性期反应。随着时间的推移，抗炎分子如白细胞介素1受体拮抗剂（IL1-Ra）的协同表达会平衡炎症介质的释放。本研究确定孕烷X受体（PXR，NR1I2）的激活是否会改变原代肝细胞培养物（PCHs）中脂多糖（LPS）诱导的基因表达程序。在从野生型小鼠分离的PCHs中预先激活PXR 24小时可抑制随后LPS诱导的关键炎症介质白细胞介素1β（IL-1β）、白细胞介素6（IL-6）和肿瘤坏死因子α（TNFα）的表达，但在从Pxr基因缺失（PXR基因敲除[KO]）小鼠分离的PCHs中则不会。PXR基因敲除小鼠的PCHs中关键炎症细胞因子的基础表达升高。与野生型小鼠相比，仅用LPS刺激PXR基因敲除小鼠的PCHs会产生更高水平的IL-1β。使用来自人源化PXR转基因小鼠以及人类供体的PCHs进行的实验表明，PXR的长期激活会随着时间的推移使细胞中IL1-Ra的分泌增加。我们的数据揭示了一个工作模型，该模型描述了PXR在抑制和解决肝细胞炎症反应中的关键作用。了解PXR如何从药物代谢酶的正调节因子转变为肝脏炎症的转录抑制因子的分子细节，将为调节肝脏和肠道炎症相关疾病提供新的药理学策略。
